GABA Effects of Nicotine in Men and Women

描述（由申请方提供）：尼古丁已被证明影响大脑中的GABA能功能。在大鼠中，尼古丁会急剧增加GABA的释放，人类和动物研究表明，GABA能系统参与尼古丁成瘾的获得和维持。在人体初步研究中，通过磁共振波谱（MRS）观察到尼古丁给药后人皮质GABA水平一过性升高。此外，已经发现尼古丁使人脑中的脑GABA合成提高2-4倍。了解急性尼古丁给药对大脑GABA的影响可能有助于深入了解吸烟与已知涉及GABA能系统的常见疾病（如抑郁症和酒精中毒）的相互作用。这个项目还可以提供更多的信息，说明为什么有些人很难戒烟。研究表明，与月经周期相关的大脑GABA水平变化会被吸烟消除，男性和女性对尼古丁的反应有所不同，因此本项目还将探讨人脑中GABA能反应的性别差异。将回答几个问题：1）急性尼古丁给药是否会增加大脑GABA？2)大脑GABA需要多长时间才能恢复到尼古丁前的水平？3)尼古丁会增加GABA的合成吗？4)性别是否影响尼古丁诱导的大脑GABA水平和合成速率的变化？将测量40名健康吸烟者（20名男性，20名女性）在戒烟过夜后脑GABA的浓度和合成速率。将进行两次测量，一次使用尼古丁吸入器，一次使用安慰剂吸入器。排除标准将包括目前的神经精神疾病，或最近的历史。公共卫生相关性：这项工作将确定大脑皮层中GABA能神经元的变化与尼古丁以及人们对尼古丁的一些主观感受有关。这些结果可能有助于解释为什么一些新的基于药物的戒烟方法是有效的，并指导新方法的开发。研究结果也可能有助于我们理解为什么抑郁症患者和酒精依赖患者更有可能对烟草成瘾。

DESCRIPTION (provided by applicant): Nicotine has been shown to affect GABAergic function in the brain. In rats, nicotine increases GABA release acutely, and human and animal studies have implicated the GABAergic system in the acquisition and maintenance of nicotine addiction. Transient increases in levels of human cortical GABA levels have been observed by magnetic resonance spectroscopy (MRS) with nicotine administration in preliminary studies in humans. Furthermore, nicotine has been seen to elevate brain GABA synthesis 2-4 fold in human brain. Knowing the effects of acute nicotine administration on brain GABA may provide insight into the interaction of tobacco smoking with prevalent disorders that are known to involve the GABAergic system, such as depression and alcoholism. This project may also provide further information about why it is so hard for some people to stop smoking. It has been shown that menstrual cycle related changes in brain GABA levels are abolished by smoking, and that men and women have some different responses to nicotine, so this project will also explore gender-based differences in GABAergic responses in the human brain. Several questions will be answered: 1) Does acute nicotine administration increase brain GABA? 2) How long does it take brain GABA to return to pre-nicotine levels? 3) Does nicotine increase GABA synthesis? 4) Does gender affect nicotine-induced changes in brain GABA levels and rates of synthesis? The concentration and rates of synthesis of brain GABA will be measured in 40 healthy smokers (20 men, 20 women) after overnight abstinence from smoking. The measurements will be conducted twice, once with a nicotine inhaler, and once with a placebo inhaler. Exclusion criteria will include current neuropsychiatric disorders, or a recent history of such. PUBLIC HEALTH RELEVANCE: This work will establish what changes in GABAergic neurons in the cerebral cortex are associated with nicotine and some of the subjective feelings that people experience with nicotine. The outcomes may help to explain why some of the newer drug-based smoking cessation approaches are effective and guide the development of new approaches. The results may also contribute to our understanding of why depressed people and patients with alcohol dependence have a greater likelihood of addiction to tobacco.